DESCRIPTION (adapted from the application) Our investigations to date indicate that inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, enzymes which produce high output nitric oxide and prostanoids, respectively, are consistently upregulated in gastrointestinal mucosal inflammation. Further, expression of these genes can regulate inflammatory pathways. We have identified important protective effects of iNOS and COX-2 in specific in vivo and in vitro models. We have also found important differences in the effects of NOS and COX-2 on inflammatory events. We have used mice with targeted deletion of either iNOS or COX-2 to assess mucosal responses to a known and common pathogen, Helicobacter pylori. iNOS deletion had no effect on H. pylori infection or the severity of gastritis. In contrast, COX-2 deletion resulted in a marked exacerbation of both acute and chronic histologic gastritis, resulted in frequent duodenal ulcer formation, which was not present in controls, and increased colonization levels of H. pylori. In addition, the tissues from H. pylori-infected COX-2-deficient [COX-2(-/-)] mice exhibited an exacerbation of the Th1-predominant, IL-12-driven dysfunctional immune response which characterizes H. pylori gastritis. COX-2 deletion was also associated with increased epithelial injury due to apoptosis. We have also confirmed these alterations of the immune response and apoptosis in vitro. The importance of understanding the role of COX-2 in different forms of GI mucosal inflammation is highlighted by the recent FDA approval and rapid utilization of multiple COX-2 selective inhibitors for treatment of musculoskeletal diseases. Based on our preliminary data and my long-standing interest in inflammatory bowel disease, in the current proposal we will determine the role of COX-2 in several important mouse models of colitis. We will use hapten models in which the mucosal immune response has been described, as well as two pertinent colonic infections, namely Helicobacter hepaticus and Citrobacter rodentia. These infection models were selected because of our findings in H. pylori gastritis and the recognition that murine IBD models appear to depend on the presence of enteric bacteria. Our specific aims are to compare COX-2(-/-) vs. (+/+) mice and wild-type mice treated with COX-2 inhibitors vs. placebo and determine the regulatory role of COX-2 in: 1. models of Th1 (TNBS) and Th2 (oxazolone) mediated colitis and 2. Colonic inflammation and injury due to H. hepaticus and C. rodentia. In both aims we will assess the effect of COX-2 on A. gross and microscopic injury; B. I1-12, Th1, pro-inflammatory and Th2 cytokine levels; and C. epithelial apoptosis. These studies are designed to establish these models and the role of COX-2 in the associated diseases, and will serve as the basis for future investigations and funding applications.